CN102304148A - Preparation method of (1R, 5R, 6S)-3-[(1R)-1-tertiary butyl dimethylsilyloxy ethane]-1-methyl-2-diphenylphosphoryloxyl-carbapenem-2-ene-3-carboxylic acid p-nitro benzyl ester - Google Patents
Preparation method of (1R, 5R, 6S)-3-[(1R)-1-tertiary butyl dimethylsilyloxy ethane]-1-methyl-2-diphenylphosphoryloxyl-carbapenem-2-ene-3-carboxylic acid p-nitro benzyl ester Download PDFInfo
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Abstract
The invention provides a preparation method of (1R, 5R,6S)-3-[(1R)-1-tertiary butyl dimethylsilyloxy ethane]-1-methyl-2-diphenylphosphoryloxyl-carbapenem-2-ene-3-carboxylic acid p-nitro benzyl ester. The preparation method comprises the following steps: respectively adding bicyclo-B1, tetrahydrofuran, 30% hydrogen peroxide and a magnetic solid base catalyst in a reaction kettle, reacting for 1-2 hours at room temperature, standing for 1 hour, and then collecting a water liquid on the lower layer; and respectively adding carbonyldiimidazole, thiophenol, a tetrahydrofuran solution of hexamethyldisilamido sodium, bromoacetic n-nitrobenzalcohol and diphenoxy o-acyl chloride in the reaction kettle, and reacting so as to obtain the target product. The preparation method has the technical advantages that the magnetic solid base catalyst is used in the reaction process, multiple components are subjected to cascade reaction; and the method has the advantages of simple process operation, good technical performance, no environment pollution and the like.
Description
Technical field
The present invention relates to the preparation of a kind of heterogeneous catalysis cascade reaction technology (1R, 5R, 6S)-3-[(1R)-1-tertiary butyl dimethyl Si ethane]-1-methyl-2-hexichol phosphinylidyne oxygen-carbon mould-2-alkene-3-carboxy acid mutual-nitro carbobenzoxy's (MAP) preparation method.
Background technology
Carbapenem antibiotic is one type of 1 the widest β-Nei Xiananleikangshengsu of antimicrobial spectrum, has has a broad antifungal spectrum, characteristics that anti-microbial activity is strong, aspect control resistant organism and zymogenic bacteria infection and immune deficiency person's infection, is bringing into play important role.The carbapenems medicine that has at present gone on the market has 6 kinds such as imipenum, panipenem, meropenem, ertapenem, S-4661 and biapenem, and wherein meropenem, ertapenem, S-4661 and biapenem are the l Beta-methyl carbapenem.Meropenem is by Dainippon Sumitomo Pharma research and development, goes on the market in Italy first in nineteen ninety-five, and it is first carbapenem antibiotic of medication separately, also is first l Beta-methyl carbapenem antibiotic simultaneously.Such microbiotic is one of important drugs of treating at present severe and multi-drug resistant bacteria infection, has obtained utilization more and more widely clinically.Therefore, the traditional technology of such medicine is improved had good economic benefit and important social benefit.
Along with the increase of environmental protection pressure and the whole society well recognized to the Sustainable Stability development, Green Chemistry more and more receives the attention of national governments, academia and enterprise in recent years.Replace liquid acid base catalysis organic reaction not only can reduce pollution with solid acid-base; Can also increase activity of such catalysts and selectivity; Simultaneously through reclaiming (regeneration) and reusing the work-ing life of improving catalyzer; Be to realize an eco-friendly important channel, solid acid alkali catalytic has become one of main contents of Green Chemistry research.
Cascade reaction has become organic chemist's research focus; Cascade reaction is claimed the domino reaction again; Be meant the process that under identical conditions, forms two keys or multikey, next step reaction of this process is after last single step reaction, so cascade reaction is the process of differentiating in a reaction times.The polycomponent cascade reaction has very big superiority with synthetic the comparing of changes traditional step, and it can reduce reactions step greatly, saves the loaded down with trivial details sepn process of a lot of complicacies.The number of Cheng Jian and to form the complicacy of molecule relevant in the quality of cascade reaction and importance and the reaction.At present, in the synthetic and asymmetric synthesis that is applied to heterogeneous ring compound of cascade reaction success, and apply to gradually and have in optically active natural product medicine synthetic.
Summary of the invention
That the object of the invention provides is a kind of (1R, 5R, 6S)-3-[(1R)-1-tertiary butyl dimethyl Si ethane]-1-methyl-2-hexichol phosphinylidyne oxygen-carbon mould-2-alkene-3-carboxy acid mutual-nitro carbobenzoxy's (MAP) preparation method.This method adopts heterogeneous catalysis cascade reaction technology, and polycomponent is carried out cascade reaction, and it is simple to have a technological operation, technological performance, advantages such as environmentally safe
The object of the present invention, this is achieved, said (1R, 5R, 6S) -3 -? [(1R) -1 - tert-butyldimethylsilyl ethylene oxide] -1 - methyl -2 - diphenyl phosphoryl oxygen - thiazol-2 - em-3 - carboxylic acid p-nitrobenzyl ester (MAP), the following structural formula: ?
Starting raw material is dicyclo B
1, chemical name be 3-{ (2R)-2-[(3S, 4R)-3-[(1R)-1-(tertiary butyl dimethyl Si) ethyl] nitrogen heterocyclic din-2-ketone-4-yl] propionyl spiral shell-[2H-1,3-benzoxazine-2,1 '-hexanaphthene]-4 (3H)-ketone, structural formula is following:
Its preparation method is in reaction kettle, adds dicyclo B respectively
1, tetrahydrofuran (THF), water is stirred in 0～10 ℃ and adds 30% ydrogen peroxide 50, magnetic solid base catalyst, room temperature reaction 1～2 hour is cooled to room temperature, leave standstill 1 hour after, emit lower layer of water liquid from the reaction kettle bottom.In reaction kettle, add carbonyl dimidazoles; 0～30 ℃ of reaction 1～2 hour; Add thiophenol,, be cooled to 0～10 ℃ 0～30 ℃ of reaction 1～2 hour; The tetrahydrofuran solution that slowly adds hmds base sodium; Reacted 0.5～1 hour, and added monobromo-acetic acid again, reacted 0.5～1 hour nitrobenzyl alcohol; Add the adjacent acyl chlorides of two phenoxy groups; 0～10 ℃ of reaction 1～2 hour, add phosphoric acid buffer, filter; Solid washs with a small amount of tetrahydrofuran (THF); Merge the tetrahydrofuran (THF) phase, saturated common salt water washing, anhydrous sodium sulfate drying; Concentrating under reduced pressure leaves standstill, and gets the solid target product.
Described magnetic solid base catalyst is the magnetic mg_al hydrotalcite solid alkali; Its preparation method is following: get a certain amount of magnetic colloidal sol and join in the reaction flask; Add distilled water again; Stirring at room; Magnesium nitrate and the aluminum nitrate getting the magnalium ratio and be 1: 2 are mixed with solution; Other joins the sodium hydroxide solution of pH=10～13; Two kinds of solution are added in the reaction flask; 110 ℃ of stirrings; Washing and drying makes magnetic mg_al hydrotalcite, forms the magnetic mg_al hydrotalcite solid alkali 450～500 ℃ of high-temperature roastings then.Magnetic colloidal sol is to adopt chemical coprecipitation, with Fe
3+And Fe
2+Vitriol or muriate in excessive alkali, mix to stir in the ratio of 1:1 and make.
The consumption of described magnetic solid base catalyst is dicyclo B
11～20% of mass percent is preferably 5～15%.
Further, described (1R, 5R, 6S)-3-[(1R)-1-tertiary butyl dimethyl Si ethane]-1-methyl-2-hexichol phosphinylidyne oxygen-carbon mould-2-alkene-3-carboxy acid mutual-nitro carbobenzoxy's (MAP) preparation method is in reaction kettle, to add dicyclo B respectively
1100 kilograms, 200 kilograms of tetrahydrofuran (THF)s, 180 kilograms in water is stirred in 0 ℃ and adds 200 kilograms in 30% ydrogen peroxide 50,10 kilograms of magnetic mg_al hydrotalcite solid alkalis, room temperature reaction 1 hour is cooled to room temperature, leave standstill 1 hour after, emit lower layer of water liquid from the reaction kettle bottom.In reaction kettle, add 30 kilograms of carbonyl dimidazoles; 30 ℃ of reactions 1 hour; Add 20 kilograms of thiophenols,, be cooled to 10 ℃ 30 ℃ of reactions 2 hours; The tetrahydrofuran solution that slowly adds hmds base sodium; Reacted 0.5 hour, and added monobromo-acetic acid again, reacted 0.5 hour nitrobenzyl alcohol; Add the adjacent acyl chlorides of two phenoxy groups; 10 ℃ of reactions 2 hours, add phosphoric acid buffer, filter; Solid washs with a small amount of tetrahydrofuran (THF); Merge the tetrahydrofuran (THF) phase, saturated common salt water washing, anhydrous sodium sulfate drying; Concentrating under reduced pressure leaves standstill, and gets solid product.
Technological merit of the present invention is: in reaction process, used magnetic solid base catalyst, polycomponent is carried out cascade reaction, it is simple to have a technological operation, technological performance, advantages such as environmentally safe.
Embodiment
Below in conjunction with embodiment the present invention is described further, but protection scope of the present invention is not limited to this.
Embodiment 1
In answering still, add dicyclo B respectively
1100 kilograms, 200 kilograms of tetrahydrofuran (THF)s, 180 kilograms in water is stirred in 0 ℃ and adds 200 kilograms in 30% ydrogen peroxide 50,10 kilograms of magnetic mg_al hydrotalcite solid alkalis, room temperature reaction 1 hour is cooled to room temperature, leave standstill 1 hour after, emit lower layer of water liquid from the reaction kettle bottom.In reaction kettle, add 30 kilograms of carbonyl dimidazoles; 30 ℃ of reactions 1 hour; Add 20 kilograms of thiophenols; 30 ℃ of reactions 2 hours, be cooled to 10 ℃, slowly add 25 kilograms of the tetrahydrofuran solutions of the hmds base sodium of 1M; Reacted 0.5 hour; Add monobromo-acetic acid again to 50 kilograms of nitrobenzyl alcohols, reacted 0.5 hour, add 20 kilograms of trimethylchlorosilanes; 38 kilograms of two phenoxy group phosphoryl chlorides; 10 ℃ of reactions 2 hours, add 100 kilograms of 2% dipotassium hydrogen phosphate damping fluids, stir; Filter; Solid washs with a small amount of tetrahydrofuran (THF), merges the tetrahydrofuran (THF) phase, the saturated common salt water washing; Anhydrous sodium sulfate drying; Concentrating under reduced pressure leaves standstill, and gets 28.6 kilograms of solid products, yield 31%.
mp：131～134℃；
1H?NMR(DMSO-d
6)δ:?0.07(s,?6H),?0.87(s,?9H),?1.20(d,?3H),?1.31(d,?3H),?3.06(m,?1H),?3.72～3.66(m,?1H),?4.14～4.23(m,?2H),?5.29～5.33(m,?2H),?7.11～7.37(m,10H)，7.5?1～7.57(m,2H)，8.19～7.23(m,2H)。
Embodiment 2
In answering still, add dicyclo B respectively
1100 kilograms, 200 kilograms of tetrahydrofuran (THF)s, 180 kilograms in water is stirred in 0 ℃ and adds 200 kilograms in 30% ydrogen peroxide 50,20 kilograms of magnetic mg_al hydrotalcite solid alkalis, room temperature reaction 1 hour is cooled to room temperature, leave standstill 1 hour after, emit lower layer of water liquid from the reaction kettle bottom.In reaction kettle, add 30 kilograms of carbonyl dimidazoles; 10 ℃ of reactions 1 hour; Add 20 kilograms of thiophenols; 10 ℃ of reactions 2 hours, be cooled to 10 ℃, slowly add 25 kilograms of the tetrahydrofuran solutions of the hmds base sodium of 1M; Reacted 0.5 hour; Add monobromo-acetic acid again to 50 kilograms of nitrobenzyl alcohols, reacted 0.5 hour, add 20 kilograms of trimethylchlorosilanes; 38 kilograms of two phenoxy group phosphoryl chlorides; 0 ℃ of reaction 1 hour, add 100 kilograms of 2% dipotassium hydrogen phosphate damping fluids, stir; Filter; Solid washs with a small amount of tetrahydrofuran (THF), merges the tetrahydrofuran (THF) phase, the saturated common salt water washing; Anhydrous sodium sulfate drying; Concentrating under reduced pressure leaves standstill, and gets 29 kilograms of solid products, yield 32%.
Embodiment 3
In answering still, add dicyclo B respectively
1100 kilograms, 200 kilograms of tetrahydrofuran (THF)s, 180 kilograms in water is stirred in 10 ℃ and adds 200 kilograms in 30% ydrogen peroxide 50,5 kilograms of magnetic mg_al hydrotalcite solid alkalis, room temperature reaction 1 hour is cooled to room temperature, leave standstill 1 hour after, emit lower layer of water liquid from the reaction kettle bottom.In reaction kettle, add 30 kilograms of carbonyl dimidazoles; 30 ℃ of reactions 1 hour; Add 20 kilograms of thiophenols; 30 ℃ of reactions 2 hours, be cooled to 10 ℃, slowly add 25 kilograms of the tetrahydrofuran solutions of the hmds base sodium of 1M; Reacted 0.5 hour; Add monobromo-acetic acid again to 50 kilograms of nitrobenzyl alcohols, reacted 0.5 hour, add 20 kilograms of trimethylchlorosilanes; 38 kilograms of two phenoxy group phosphoryl chlorides; 10 ℃ of reactions 2 hours, add 100 kilograms of 2% dipotassium hydrogen phosphate damping fluids, stir; Filter; Solid washs with a small amount of tetrahydrofuran (THF), merges the tetrahydrofuran (THF) phase, the saturated common salt water washing; Anhydrous sodium sulfate drying; Concentrating under reduced pressure leaves standstill, and gets 28 kilograms of solid products, yield 30%.
Claims (2)
1. one kind (1R, 5R, 6S)-3-[(1R)-1-tertiary butyl dimethyl Si ethane]-1-methyl-2-hexichol phosphinylidyne oxygen-carbon mould-2-alkene-3-carboxy acid mutual-nitro carbobenzoxy's preparation method, its structural formula is following:
It is characterized in that the preparation method is: in reaction kettle, add dicyclo B respectively
1, tetrahydrofuran (THF), water; Be stirred in 0～10 ℃ and add 30% ydrogen peroxide 50, magnetic solid base catalyst, room temperature reaction 1～2 hour; Be cooled to room temperature, leave standstill 1 hour after, emit lower layer of water liquid from reaction kettle bottom; In reaction kettle, add carbonyl dimidazoles,, add thiophenol 0～30 ℃ of reaction 1～2 hour; 0～30 ℃ of reaction 1～2 hour; Be cooled to 0～10 ℃, slowly add the tetrahydrofuran solution of hmds base sodium, reacted 0.5～1 hour; Add monobromo-acetic acid again to nitrobenzyl alcohol; Reacted 0.5～1 hour, and added the adjacent acyl chlorides of two phenoxy groups, 0～10 ℃ of reaction 1～2 hour; Add phosphoric acid buffer; Filter, solid washs with a small amount of tetrahydrofuran (THF), merges the tetrahydrofuran (THF) phase; The saturated common salt water washing; Anhydrous sodium sulfate drying, concentrating under reduced pressure leaves standstill, and gets the solid target product; Described magnetic solid base catalyst is the magnetic mg_al hydrotalcite solid alkali, and the consumption of described magnetic solid base catalyst is dicyclo B
11～20% of mass percent.
2. described magnetic solid base catalyst is the magnetic mg_al hydrotalcite solid alkali; Its preparation method is following: get a certain amount of magnetic colloidal sol and join in the reaction flask; Add distilled water again; Stirring at room; Magnesium nitrate and the aluminum nitrate getting the magnalium ratio and be 1: 2 are mixed with solution; Other joins the sodium hydroxide solution of pH=10～13; Two kinds of solution are added in the reaction flask; 110 ℃ of stirrings; Washing and drying makes magnetic mg_al hydrotalcite; Form the magnetic mg_al hydrotalcite solid alkali 450～500 ℃ of high-temperature roastings then, magnetic colloidal sol is to adopt chemical coprecipitation, with Fe
3+And Fe
2+Vitriol or muriate in excessive alkali, mix to stir in the ratio of 1:1 and make.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103012471A (en) * | 2012-12-17 | 2013-04-03 | 凯莱英医药集团（天津）股份有限公司 | Method for preparing key intermediate of beta-methylcarbapenem antibiotic |
| CN114685920A (en) * | 2022-05-13 | 2022-07-01 | 安徽康采恩包装材料有限公司 | Degradable packaging material and synthesis method thereof |
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| WO2002012230A1 (en) * | 2000-08-10 | 2002-02-14 | Dong Wha Pharm. Ind. Co., Ltd. | Intermediate of carbapenem antibiotics and process for the preparation thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103012471A (en) * | 2012-12-17 | 2013-04-03 | 凯莱英医药集团（天津）股份有限公司 | Method for preparing key intermediate of beta-methylcarbapenem antibiotic |
| CN114685920A (en) * | 2022-05-13 | 2022-07-01 | 安徽康采恩包装材料有限公司 | Degradable packaging material and synthesis method thereof |
| CN114685920B (en) * | 2022-05-13 | 2023-09-26 | 安徽康采恩包装材料有限公司 | Degradable packaging material and synthesis method thereof |
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